The present invention relates to an improved delivery system for the administration of large-molecule pharmaceuticals, e.g. peptidic drugs, vaccines and hormones. In particular it relates to pharmaceuticals which may be administered by means of an aerosol into the mouth, for buccal or pulmonary application.
Sub-optimal disease management for respiratory illnesses, e.g. asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) collectively represents about billion dollar worldwide market for biotechnology-derived proteins. The pulmonary delivered protein, represent an enormous market opportunity for pulmonary drug delivery. The delivery of drugs via inhalation for local delivery to the upper lung (most commonly in the form of metered-dose inhalers) and for systemic delivery (into the bloodstream) via the deep lung defines the scope of pulmonary drug delivery, is the subject of intense research.
For more than a decade, companies have searched extensively to find a drug delivery technology which is patient-friendly, non-invasive, and an economically viable alternative to injecting the large macromolecule proteins. Some of the earliest efforts involved transdermal delivery via electroporations but this has mostly been abandoned as large molecules simply can""t pass through the skin. Oral delivery, which would clearly be the preferable dosage form, has had some success, but a major obstacle is the degradation and denaturization of proteins in the gastrointestinal tract.
Drug delivery through the lung appears optimal for two major reasons, i.e. the enormous surface area available for delivery, and permeability to large molecules. The lung has about a half billion alveoli. The alveoli in an average adult lung have a surface area the size of a tennis court, far exceeding the surface area of most other delivery routes, e.g. GI tract, by several orders of magnitude. The alveoli allow oxygen and other molecules to readily pass into the circulatory system. Conventional metered dose inhalers, primarily used for asthma, deliver drugs into the upper branches of the lung. In terms of permeability, the buccal cavity and lung are ideal absorption areas for both small and large molecules. Large proteins, including antibodies, are readily absorbed through the alveoli either directly into the circulatory system or, more frequently, via the lymphatic system, which subsequently releases the drug into the bloodstream.
The ability to deliver large molecule drugs orally (buccally) and/or into the deep lung will represent one of the most significant technical breakthroughs in drug delivery.
New products that address these drug delivery needs are sought, which simultaneously provide patients with a convenient user friendly mechanism and physicians with a tool to improve therapy, compliance, and to prevent or reduce expensive hospital stays.
The absorption of proteins and peptides is believed to be enhanced by the diffusion of large molecules entrapped in droplet form through the aqueous pores and the cell structure perturbation of the tight paracellular junctions. In order to further improve the penetration and absorption of formulation it has now been found that such formulations can be mixed with a propellant (preferably a non-CFC) and delivered, e.g. applied to the buccal mucosa, through metered dose inhalers (MDIs) or similar. The present invention uses novel formulations that are intended to improve the quality (in terms of absorption), stability, and performance of MDI-delivered pharmaceuticals. A novel method is used to solubilize drugs in a propellant. The formulation ingredients are selected specifically to give enhancement in the penetration through the pores and facilitate the absorption of the drugs to reach therapeutic levels in the plasma.
With previous formulations, in order to administer the pharmaceutical agent, it is necessary to shake the vial in order to temporarily intimately mix the two phases, so that a mixture of pharmaceutical formulation and propellant are expelled from the vial upon opening a dosing valve. The propellant and pharmaceutical phases quickly separate after shaking. Separation of the phases may lead to situations wherein the person administering the drug does not shake the vial sufficiently, forgets to shake the vial or waits too long before opening the dosing valve. Such situations lead to a lack of uniformity in the amount of pharmaceutical being administered from one opening of the valve to the next, i.e. from xe2x80x9cshotxe2x80x9d to xe2x80x9cshotxe2x80x9d. This is particularly problematic where the amount of pharmaceutical agent to be administered is critical, e.g. with insulin and some pain killing drugs and narcotics. It is desirable, therefore, for the formulation and propellant to be evenly mixed, e.g. as a solution, stable suspension or the like.
The present invention is directed to providing a stable mixture of propellant and pharmaceutical agent.
The terms xe2x80x9ccomprisingxe2x80x9d and xe2x80x9ccomprisesxe2x80x9d when used in this specification are taken to specify the presence of the stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
The term xe2x80x9csolubilizedxe2x80x9d is used in this specification to refer to a stable intimate mixture of ingredients. It has not been determined whether the mixture is a solution, suspension or other form of intimate mixture. Such a solubilized mixture is stable for substantial periods of time, e.g. months, without separation.
Accordingly the present invention provides a pressurized container containing a stable solubilized mixture of propellant which is liquid under pressure and an intermediate formulation which comprises a pharmaceutical agent, water, first ingredient, second ingredient and at least one third ingredient, wherein the first ingredient is selected from glycerin and polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation, the second ingredient is selected from phenol, methyl phenol and mixtures thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation, each third ingredient is selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxo-cholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chamomile extract, cucumber extract, borage oil and evening of primrose oil and mixtures thereof, in an amount of from 1-50 wt./wt % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients is less than 90 wt./wt % of the intermediate formulation.
In one embodiment, the alkali metal C8 to C22 alkyl sulphate is in a concentration of from 2 to 20 wt./wt. % of the intermediate formulation, especially 5 to 15 wt./wt. %.
In a further embodiment, the methyl phenol is m-cresol.
In another embodiment, the alkali metal C8 to C22 alkyl sulphate is sodium lauryl sulphate.
In a further embodiment the polidocanol alkyl ether is a polidocanol 10 or 20 lauryl ether.
In another embodiment, the polyoxyethylene ether is polyoxyethylene sorbitan ether, and particularly polyoxyethylene sorbitan 80 lauryl ether.
In yet another embodiment, the third ingredient is present in a concentration of from about 1 to about 25 wt./wt. %.
In yet another embodiment, the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane.
In a further embodiment, the weight ratio of intermediate formulation to propellant is from 5:95 to 25:75.
In one embodiment, the pharmaceutical agent, water, first, second and third ingredients and propellant have been solubilized by a process comprising the steps of:
a) dissolving the pharmaceutical agent in water and adjusting the pH to a level suitable for pharmaceutical use;
b) mixing with the first ingredient in an amount of from 1-50 wt./wt. % of the intermediate formulation;
c) then mixing with the second ingredient in an amount of from 1-20 wt./wt. % of the intermediate formulation;
d) subsequently adding and mixing at least one third ingredient to form the intermediate formulation;
e) charging the intermediate formulation to a pressurizable container and subsequently charging the container with the propellant.
The invention also provides a process for making a stable aerosol pharmaceutical composition in which a propellant and an intermediate formulation, which comprises a pharmaceutical agent, water and first, second and third ingredients, has been solubilized by a process comprising the steps of:
a) dissolving the pharmaceutical agent in water and adjusting the pH to a level suitable for pharmaceutical use;
b) mixing with a first ingredient selected from glycerin, polyglycerin and mixtures thereof in an amount of from 1-50 wt./wt. % of the intermediate formulation;
c) then mixing with a second ingredient selected from phenol, methyl phenol and mixtures thereof in an amount of from 1-20 wt./wt. % of the intermediate formulation;
d) subsequently adding and mixing at least one third ingredient to form the intermediate formulation, said third ingredient being selected from the group consisting of alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxocholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chamomile extract, cucumber extract, borage oil and evening of primrose oil and mixtures thereof, each of said third ingredients being present in an amount of from 1-50 wt./wt % of the intermediate formulation, and wherein the total concentration of first, second and third ingredients are less than 90 wt./wt % of the intermediate formulation;
e) charging the intermediate formulation to a pressurizable container and subsequently charging the container with the propellant.
In one embodiment, the alkali metal C8 to C22 alkyl sulphate is in a concentration of from 2 to 25 wt./wt. % of the intermediate formulation.
In a further embodiment, the methyl phenol is m-cresol.
In another embodiment, the alkali metal C8 to C22 alkyl sulphate is sodium lauryl sulphate.
In a further embodiment the polidocanol alkyl ether is a polidocanol 10 or 20 lauryl ether.
In another embodiment, the polyoxyethylene ether is polyoxyethylene sorbitan ether, particularly polyoxyethylene sorbitan 80 lauryl ether.
In yet another embodiment, the third ingredient is present in a concentration of from about 1 to about 25 wt./wt. %.
In another embodiment, in step a) the pH is adjusted to between 6.0 and 9.0, and preferably between 7.0. and 8.0.
In yet another embodiment, the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane.
In a further embodiment, the weight ratio of intermediate formulation to propellant is from 5:95 to 25:75.
In yet another embodiment, step d) is accomplished with a high speed mixer or sonicator.
The present invention provides an improved, stable formulation. The formulation allows delivery of macromolecular (high molecular weight) pharmaceutical agents, particularly through the membranes in the mouth or lungs.
The pharmaceutical agents cover a wide spectrum of agents, including proteins, peptides, hormones, vaccines and drugs. The molecular weights of the macromolecular pharmaceutical agents are preferably above 1000, especially between 1000 and 2 000 000.
The proteinic pharmaceutical agent may be selected from a wide variety of macromolecular agents, depending on the disorder being treated, generally with molecular weights greater than about 1000 and especially between about 1000 and 2 000 000. Preferred pharmaceutical agents are selected from the group consisting of insulin, heparin, low molecular weight heparin, hirulog, hirugen, huridine, interferons, interleukins, cytokins, mono and polyclonal antibodies, immunoglobins, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, insulin like growth factors (IGF), glucagon like peptides (GLP-1), large molecule antibiotics, protein based thrombolytic compounds, platelet inhibitors, DNA, RNA, gene therapeutics and antisense oligonucleotides and many injectable opiods, narcotics, hypnotics, steroids and pain killers (non-steroidal anti-inflammatory drugs).
For insulin-containing and some other compositions, the composition may also contains at least one inorganic salt which helps to open channels in the membranes of the mouth or lungs, and may provide additional stimulation to release insulin. Non-limiting examples of inorganic salts are sodium, potassium, calcium and zinc salts, especially sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate.
It will be recognized by those skilled in the art that for many pharmaceutical compositions it is usual to add at least one antioxidant to prevent degradation and oxidation of the pharmaceutically active ingredients. It will also be understood by those skilled in the art that colorants, flavouring agents and non-therapeutic amounts of other compounds may be included in the formulation. Typical flavouring agents are menthol, sorbitol and fruit flavours.
The antioxidant may be selected from the group consisting of tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben and ascorbic acid and mixtures thereof. A preferred antioxidant is tocopherol.
In a preferred embodiment at least one protease inhibitor is added to the formulation to inhibit degradation of the pharmaceutical agent by the action of proteolytic enzymes. Of the known protease inhibitors, most are effective at concentrations of from 1 to 3 wt./wt. % of the formulation.
Non-limiting examples of effective protease inhibitors are bacitracin, soyabean trypsin, aprotinin and bacitracin derivatives, e.g. bacitracin methylene disalicylate. Bacitracin is the most effective of those named when used in concentrations of from 1.5 to 2 wt./wt. %. Soyabean trypsin and aprotinin two may be used in concentrations of about 1 to 2 wt./wt. % of the formulation.
The amount of the first ingredient is present in a concentration of from 1 to 50 wt/wt % of the intermediate formulation. The amount of the second ingredient is present in a concentration of from 1 to 20 wt/wt % of the intermediate formulation and the third ingredient is present in a concentration of from 1 to 50 wt/wt % of the intermediate formulation, and total concentration of such ingredients is less than 90 wt./wt % of the formulation. It is believed that the phenolic compounds act mainly as preservatives and complexing agents to stabilize drugs, e.g. insulin. Besides their function as a stabilizer and preservative, they may also act as antiseptic agents and furthermore may help in absorption. The methyl phenol may be o-cresol, m-cresol or p-cresol, but m-cresol is preferred.
The order of addition of the ingredients in the formulation are important in order to obtain a stable mixture. First, the pharmaceutical agent is dissolved in water. Preferably, the pH is adjusted to between about 6.0 and 9.0, and even more preferably to between about 7.0 and 8.0. Secondly, the aqueous pharmaceutical agent mixture is mixed first with glycerin, polyglycerin or mixtures thereof (the first ingredient), and then with phenol, methyl phenol or mixtures thereof (the second ingredient). Subsequently the third ingredient is added and mixed to form the intermediate formulation. The third ingredient is at least one of the following compounds: alkali metal C8 to C22 alkyl sulphate, polidocanol C6 to C40 alkyl ethers, trihydroxy oxocholanyl glycines and pharmaceutically acceptable salts thereof, polyoxyethylene ethers, alkyl-aryl polyether alcohols, hyaluronic acid and pharmaceutically suitable salts thereof, monoolein, triolein, lysine, polylysine, oleic acid, linoleic acid, linolenic acid, monooleates and laurates, glycolic acid, lactic acid, chamomile extract, cucumber extract, borage oil and evening of primrose oil. The ingredients are mixed together with a mixer. When the third ingredient is added, a high speed mixer or sonicator is preferred. The resulting mixture is referred to herein as the intermediate formulation.
Each of the non-pharmaceutical substances referred to in the previous paragraph may be added in concentrations previously indicated, provided that the total amount of such substances does not exceed 90 wt./wt. % of the intermediate formulation.
After formation of the intermediate formulation, the formulation is charged to a pressurizable container. Preferably the container is a vial suitable for use with a metered dose inhaler or applicator. Then the vial is charged with propellant. As the propellant is introduced into the vial, there is great turbulence in the vial and the propellant and pharmaceutical formulation become intimately mixed and do not separate on standing. It is believed that the propellant and pharmaceutical mixture so formed would be stable for several months. As a result, it is not necessary to shake the vial before use, although, through habit with other formulations, many users may shake the vial. The advantage of the solubilized formulation will be immediately apparent to those skilled in the art. For example, the relative homogeneity of the mixture provides good accuracy of pharmaceutical dispensing from xe2x80x9cshotxe2x80x9d to xe2x80x9cshotxe2x80x9d and from the first shot to the last from the container. As is known, in order to deliver the pharmaceutical agent to the lung, it is necessary for the user to breathe deeply when the aerosol spray from the pressurized container is released. Without breathing in, the pharmaceutical agent is delivered to the buccal cavity. The method chosen will depend on a number of factors, including the type of pharmaceutical agent, the concentration in the aerosol, the desired rate of absorption required and the like.
A particular advantage with the use of metered dose applicators or inhalers is that the formulation can be delivered in a relatively precise dose, e.g. titratable to injection within 1 unit of insulin dose. The droplet size of the formulation preferably falls between 1-5 xcexcm in order for droplets to penetrate buccal mucosa or to reach to the deep lung surface. Thus, the present invention is suitable for delivery of proteinic drugs such as insulin for the treatment of diabetes.
The pressurized inhalers also offer a wide dosing range and consistent dosing efficiency. With such a delivery, greater than about 95% of the dose may reach the target area. The smaller particle size (1-5 xcexcm) obtained using pressurized inhalers also enhances dosing due to broader coverage within the lung cavity. In this situation, increased coverage can help more absorption of a drug like insulin. Furthermore, because these devices are self-contained, potential contamination is avoided.
The amount of physiologically peptide or protein in the compositions of this invention is typically a quantity that provides an effective amount of the drug to produce the physiological activity (therapeutic plasma level) for which peptide or protein is being administered. In consideration of the fact that the bioavailability of any active substance can never be 100%, that is to say the administered dose of the active drug is not completely absorbed, it is preferable to incorporate slightly larger amount than the desired dosage. Where the dosage form is a spray (aerosol) or the like which is repeatedly dispensed from the same container, it is preferably so arranged that the unit dose will be slightly greater than the desired dose. It should be understood that dosage will vary with species of warm blood animals such as man, domestic animals, and their body weights. The utilization of atomizer or aerosol spray devices (metered dose inhalers or nebulizers) is important to provide particle sizes for effective absorption from the nasal or lung cavity so the drug may successfully absorbed or reach to the specific site. It is believed that a variety of proteins retain their biological activity even after prolonged exposure to propellants commonly used in metered dose inhalers.